Over 35 million people in the United States are affected by diabetes and glucose intolerance. These individuals carry up to eight times the risk of cardiovascular events compared to non-diabetic individuals, making cardiovascular disease the largest cause of mortality in this population. Diabetic patients suffer from accelerated atherosclerosis and also exhibit a diminished angiogenic response to myocardial ischemia. Angiogenic therapy using growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2), which has been shown to improve coronary flow and left ventricular dysfunction in numerous animal models, is a particularly attractive therapeutic option for diabetic patients with end-stage coronary artery disease (CAD). However, clinical trials have failed to demonstrate the efficacy of therapeutic angiogenesis in patients with advanced CAD. Although some studies in mice and in vitro have pointed to possible mechanisms explaining the lack of angiogenesis response in diabetes, the validation and extension of these concepts in large animal studies is an essential prerequisite to their application in humans. This research project aims to study the effects of diabetes and resulting endothelial dysfunction on endogenous and growth factor induced myocardial angiogenesis in a well-established pre-clinical porcine model of chronic myocardial ischemia. The focus of the research will be on functional changes in collateral- dependent flow, vascular density, and microvascular function, as well as key molecular events involved in the altered angiogenic process in-vivo. Two models of diabetes will be produced: 1) Yucatan miniswine, using streptozotocin (STZ), (a drug that kills pancreatic cells producing insulin) will create a model that mimics many of the abnormalities present in type I diabetic patients, and 2) Ossabaw swine fed an atherogenic diet that will develop a glucose intolerance and insulin resistance similar to type II diabetes. In both models we will induce an endogenous angiogenic response by creating a chronic myocardial ischemia. We proposed to determine: The endogenous functional angiogenic response to chronic myocardial ischemia as well as on the molecular pathways involved in myocardial angiogenesis in STZ-induced diabetes (Aim 1) and in Genotypic / diet induced glucose intolerance and insulin resistance (Aim 2). The influence of STZ-induced diabetes on the growth factor induced functional angiogenic response to perivascular FGF-2 and VEGF therapy as well as the molecular pathways involved will be studied in Aim 3. Aim 4 will study the effect of glycemic control (i.e. maintenance of plasma glucose less than 150 mg/dL) on the endogenous and growth factor induced functional angiogenic response to chronic myocardial ischemia on STZ-induced diabetes. We hope that the results of these studies will bring important insights about the mechanisms inhibiting chronic ischemia induced endogenous angiogenesis and the response to exogenous factors in more relevant animal models of diabetes.